The objective of the proposed research is to elucidate the cellular mechanism of regulation of fetal hemoglobin synthesis in man. Our aims are a) to investigate the regulation of fetal hemoglobin in the adult and specifically the relationship between fetal hemoglobin synthesis and the process of differentiation of the adult erythroid cells; this will be pursued with studies of patients with activated HbF synthesis, studies of Hb F synthesis in baboons following acute perturbations of erythropoiesis, experiments using recloning and long term cultures of adult hemopoietic cells and studies of factors which induce Hb F synthesis or have a concurrent effect on Hb F and the differentiation of erythroid progenitors. b) To study the mechanism of switching from fetal to adult hemoglobin formation during development with emphasis on detection of cell-environment interactions which may underly the developmental switching of hemoglobins. c) To examine whether and how the asynchronous synthesis of fetal and adult hemoglobins during maturation of erythroblasts relate to the mechanism of hemoglobin switching. It is hoped that through these studies a better understanding of the cellular control of fetal hemoglobin synthesis in man will be achieved. An understanding of the mechanism of the cellular Hb F regulation may have clinical implications since it may eventually lead to therapeutic induction of Hb F synthesis in patients with sickle cell or thalassemia syndromes.